One of the major limitations on the overall management of lung cancer is that we lack a proven strategy for early detection. Our goal is to use biomarkers predictive of cancer development to detect lung cancer early while cure remains possible. The central hypothesis of this proposal is that the bronchial epithelium acquires molecular abnormalities before the invasive stage and that specific genes and proteins may be used as biomarkers for early detection of lung cancer. To test this hypothesis, we propose the following aims: Specific Aim 1. To identify new molecular abnormalities specific to the development of squamous carcinoma of the lung. We propose to take a combined genetic and proteomic approach to discover the determinants of squamous carcinoma development. From these studies in normal bronchial epithelium, preinvasive and invasive lesions using high-density genomic array, matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) and custom oligonucleotide array, we will carefully select candidate biomarkers to be tested in Aim 2. Specific Aim 2. To determine the prevalence of candidate biomarkers in lung cancer progression and to calculate the odds of developing lung cancer according to biomarkers status in preinvasive lesions. FISH and IHC applied to tissue microarray sections enable high- throughput analysis of molecular alterations that may contribute to cancer development and progression. Specific Aim 3. To determine the odds of developing lung cancer according to proteomic biomarker status in the normal bronchial epithelium of high-risk individuals. We will test those in a unique set of bronchial specimens obtained prospectively in a cohort of high-risk individuals, some of whom developed lung cancer. In summary, we are proposing to interrogate the human squamous tumorigenesis model by genetic and protein approaches, identify candidate genes involved in tumorigenesis and test their potential role as biomarkers predictive of lung cancer development.